Project 3 of our Program Project is entitled lon Channels in Afferent Sensitization and Detrusor Overactivity (Project Director: Naoki Yoshimura, Department of Urology). The following key aims will utilize unique and innovative expertise, available in our institutions, to understand the pathophysiology of detrusor overactivity (DO) and detrusor sphincter dyssynergia (DSD), especially by targeting afferent hyperexcitability, which has been proposed as one of the important mechanisms underiying lower unnary tract dysfunction in chronic spinal cord injury (SCI). First, we will study the correlated changes in bladder activity (i.e., DO) and the expression and functional properties of K^ ion channels after SCI as we have previously found that altered expression of voltage-gated K* channels is one of the key events for the induction of C-fiber hyperexcitability resulting in bladder overactivity. Secondly, we will investigate changes in the K^ and Ca^* ion channel mechanisms in pudendal afferent pathways innervating the urethra containing external urethral sphincter (EUS), and their correlation with urethral hyperactivity (i.e., DSD) after SCI as there are no previous studies that examined the SCI-induced changes in functional properties of pudendal afferent neurons innervating the urethra. Lastly, we will investigate the roles of nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) and p38 MAPK signaling in neuroplasticity of bladder and urethral afferent pathways that underlies SCI-induced DO and DSD. We will also utilize the small-interfenng RNA technique to identify molecular correlates in K* ion channel subunits that induce bladder and urethral afferent hyperexcitability. The long-term objectives of the research program are to establish new and effective therapeutic targets and/or interventions strategies for the treatment of urological problems in spinal cord disorders. There is significant synergy especially with Projects 1 and 4, which will respectively examine peripheral afferent remodeling and spinal mechanisms controlling EUS function. Project 3 also maximizes the uses of the resources of Animal and Optical Imaging Cores. RELEVANCE (See instmctions): Following spinal cord injury, increased excitability of bladder and urethral afferents lead to overactivity. Determining the ion channel mechanisms involved and preventing changes in their expression by anti-growth factor treatment could lead to a new method to prevent/treat LUT dysfunction.